Intracranial aneurysms (IA) affect ~2% of the population and cause 500,000 hemorrhagic strokes annually in relatively young patients (median age 50), resulting in death and severe neurological impairment. The pathogenesis of aneurysm formation and rupture is unknown, and pre-morbid identification is essential to prevent catastrophic hemorrhage. We have recently completed a multistage genome-wide association study (GWAS) with over 2,100 IA patients and 8,000 controls and identified common SNPs on chromosomes 2, 8 and 9 that surpass stringent thresholds and replicate association with IA (odds ratios 1.24 - 1.36). In this initial study, we also found evidence for several other IA susceptibility loci showing P values less than10-4, carrying modest odds ratios (OR<1.25) and likely contributing to IA risk in a cumulative fashion. In order to increase our power to detect and confirm these loci, we have recruited over 5,100 new cases and 22,000 controls bringing the total number of cases and controls over 7,300 and 30,500. The major emphasis of this proposal is to take our GWAS results to the next stage by identifying the causative alleles in each locus so that the IA genes can be confirmed. Discovery of these genes will lead in future applications to hypothesis driven research aimed at understanding the function of these transcripts and gaining mechanistic insight into IA pathophysiology. Our effort in this application can be divided into three conceptually distinct but complementary efforts: 1) we will characterize the specific functional variation at each locus accounting for the common variant findings, identified through our prior GWAS;2) we will evaluate the potential contribution of both rare and common structural variation to IA, and 3) we will seek to identify evidence for additional variants contributing to IA. The end result of these analyses will be a comprehensive view of the genetic architecture of this disorder focusing on common alleles that will serve as the launching point for biological studies of IA and begin creating an opportunity to identify genetically at-risk individuals prior to any morbid events such as IA rupture. PUBLIC HEALTH RELEVANCE: Intracranial aneurysms (IA) affect ~2% of the population and cause 500,000 hemorrhagic strokes annually in relatively young patients (median age 50), resulting in death and severe neurological impairment. The pathogenesis of aneurysm formation and rupture is unknown, and there is evidence to suggest that genetic factors play a role both in formation and rupture. We have recently completed a large scale genetics project that included DNA samples from 2,100 IA patients and 8,000 controls and identified 3 chromosomal regions that carry aneurysm genes. We now propose to do follow-up studies to identify these aneurysm genes and continue to search for additional ones.